This application addresses broad Challenge Area (04) Clinical Research and specific Challenge Topic, 04-HL- 101: Identifying Mechanisms Linking Cardiopulmonary Disease Risk and Sleep-Disordered Breathing (SDB). SDB is a common condition that affects approximately 5% of all middle-aged and older adults. It is characterized by recurrent collapse of the upper airway during sleep and is associated intermittent hypoxemia and recurrent arousals. Research over the last few years has shown that SDB is independently associated hypertension and cardiovascular disease. However, causal mechanisms underlying these associations are still not clear. Intermittent hypoxemia, a pathognomonic feature of SDB, is known to trigger a cascade of signaling pathways including endothelin-1 (ET-1) and increasing the propensity for insulin resistance, glucose intolerance and type 2 diabetes. The overarching goal of this proposal is to characterize the mechanisms through which SDB may lead to alterations in glucose metabolism and determine the putative role of ET-1. To accomplish our goals, we will employ a combination of unique observational and interventional human studies, in vivo and ex vivo intermittent hypoxia protocols, and molecular biological approaches to elucidate the direct effects of intermittent hypoxia on glucose metabolism. Our specific aims are as follows. AIM 1: To determine the effects of SDB and intermittent hypoxia on insulin sensitivity, insulin secretion and circulating ET-1 levels. We will demonstrate that: (a) ET-1 levels will be elevated in patients with SDB and that these levels will be determined by the degree of nocturnal hypoxemia and predict the severity of insulin resistance and impaired insulin secretion;and (b) exposure to short-term intermittent hypoxia, in normal subjects, will increase ET-1 and impair insulin sensitivity and secretion. AIM 2: To determine whether intermittent hypoxia-induced changes in the ET-1 pathway contribute to alterations in insulin sensitivity and secretion. We hypothesize that, in a murine model, exposure to intermittent hypoxia will: (a) decrease insulin sensitivity and insulin secretion;(b) increase circulating ET-1 levels;(c) ET-1 receptor antagonists will prevent hypoxia-induced alterations in glucose metabolism. AIM 3: To evaluate whether intermittent hypoxia exerts a direct effect on islet cell function and whether this is mediated by ET-1. We hypothesize that insulin secretion will be: (a) impaired by exposure to intermittent hypoxia, and (b) unaltered by intermittent hypoxia in the presence of ET-1 antagonists. The experiments outlined in this application will provide important mechanistic insight into the causal pathways that may link SDB and metabolic dysfunction and cardiovascular disease. IMPACT: Every year Johns Hopkins Institutions directly generate about $10 billion in economic activity in the State of Maryland, a 43% increase from the $7 billion generated in 2002 and the equivalent of one of every twenty-four dollars in the state's economy today. In 2008, Johns Hopkins Institutions provided 45,000 jobs and created 700 new jobs each year since 2002. Directly and indirectly Johns Hopkins Institutions support more than 100,000 jobs in Maryland, one of every 29 in the state. In Baltimore City alone Johns Hopkins directly and indirectly supports 60,000 jobs, or 16.7% of all City employment. This application will create three jobs. PUBLIC HEALTH RELEVANCE: Sleep-disordered breathing is a common condition that affects more than 12 million adults in the US and has been associated with daytime sleepiness, high blood pressure, cardiovascular disease, and diabetes. The overall objective of this research proposal is to determine how sleep-disordered breathing leads to insulin resistance and defects in insulin secretion from the pancreas, which in turn can increase the future risk for cardiovascular disease.